The DNA damage response (DDR) is a designation for a number of pathways that protects
our DNA from various damaging agents. In normal cells, the DDR is extremely important for
maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced
DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer
treatments. Hyperthermia is an example of such a treatment—it inhibits a sub-pathway of the
DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of
BRCA2 —one of the key HR factors. Understanding the precise mechanism that mediates this
degradation is important for our understanding of how hyperthermia affects therapy and how
homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the
process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance
the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving
hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily
conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in
directly targeting BRCA2 for protein degradation via the proteasome, and that BRCA2 degradation
might be modulated by oxidative stress and radical scavengers